Aplidine (Dehydrodidemnin B) is a cyclic depsipeptide that was isolated from a Mediterranean marine tunicate, Aplidium albicans, and it is the subject of WO 9109485. It is related to compounds known as didemnins, and has the following structure:

More information on aplidine, aplidine analogues, their uses, formulations and synthesis can be found in patent applications WO 98 1352, WO 99 42125, WO 01 76616, WO 01 35974, WO 02 30441 and WO 02 02596. We incorporate by specific reference the content of each of these PCT texts.
In both animal and human preclinical studies and in clinical Phase I studies this agent has been shown to have cytotoxic potential against a broad spectrum of tumor types including leukemia and lymphoma. See for example:    Faircloth, G. et al.: “Dehydrodidemnin B (DDB) a new marine derived anticancer agent with activity against experimental tumour models”, 9th NCI-EORTC Symp New Drugs Cancer Ther (March 12-15, Amsterdam) 1996, Abst 111;    Faircloth, G. et al.: “Preclinical characterization of aplidine, a new marine anticancer depsipeptide”, Proc Amer Assoc Cancer Res 1997, 38: Abst 692;    Depenbrock H, Peter R, Faircloth G T, Manzanares I, Jimeno J, Hanauske A R.: “In vitro activity of Aplidine, a new marine-derived anti-cancer compound, on freshly explanted clonogenic human tumour cells and haematopoietic precursor cells” Br. J. Cancer, 1998; 78: 739-744;    Faircloth G, Grant W, Nam S, Jimeno J, Manzanares I, Rinehart K.: “Schedule-dependency of Aplidine, a marine depsipeptide with antitumor activity”', Proc. Am. Assoc. Cancer Res. 1999; 40: 394;    Broggini M, Marchini S, D'Incalci M, Taraboletti G, Giavazzi R, Faircloth G, Jimeno J.: “Aplidine blocks VEGF secretion and VEGF/VEGF-R1 autocrine loop in a human leukemic cell line”, Clin Cancer Res 2000; 6 (suppl): 4509;    Erba E, Bassano L, Di Liberti G, Muradore I, Chiorino G, Ubezio P, Vignati S, Codegoni A, Desiderio M A, Faircloth G, Jimeno J and D'Incalci M.: “Cell cycle phase perturbations and apoptosis in tumour cells induced by aplidine”, Br J Cancer 2002; 86: 1510-1517;    Paz-Ares L, Anthony A, Pronk L, Twelves C, Alonso S, Cortes-Funes H, Celli N, Gomez C, Lopez-Lazaro L, Guzman C, Jimeno J, Kaye S.: “Phase I clinical and pharmacokinetic study of aplidine, a new marine didemnin, administered as 24-hour infusion weekly” Clin. Cancer Res. 2000; 6 (suppl): 4509;    Raymond E, Ady-Vago N, Baudin E, Ribrag V, Faivre S, Lecot F, Wright T, Lopez Lazaro L, Guzman C, Jimeno J, Ducreux M, Le Chevalier T, Armand J P.: “A phase I and pharmacokinetic study of aplidine given as a 24-hour continuous infusion every other week in patients with solid tumor and lymphoma”, Clin. Cancer Res. 2000; 6 (suppl): 4510;    Maroun J, Belanger K, Seymour L, Soulieres D, Charpentier D, Goel R, Stewart D, Tomiak E, Jimeno J, Matthews S.:“Phase I study of aplidine in a 5 day bolus q 3 weeks in patients with solid tumors and lymphomas”, Clin. Cancer Res. 2000; 6 (suppl): 4509;    Izquierdo M A, Bowman A, Martinez M, Cicchella B, Jimeno J, Guzman C, Germa J, Smyth J.: “Phase I trial of Aplidine given as a 1 hour intravenous weekly infusion in patients with advanced solid tumors and lymphoma”, Clin. Cancer Res. 2000; 6 (suppl): 4509.
Mechanistic studies indicate that aplidine can block VEGF secretion in ALL-MOLT4 cells and in vitro cytotoxic activity at low concentrations (5nM) has been observed in AML and ALL samples from pediatric patients with de novo or relapsed ALL and AML. Aplidine appears to induce both a G1, and a G2 arrest in drug treated leukemia cells in vitro. Apart from down regulation of the VEGF receptor, little else is known about the mode(s) of action of aplidine.
In phase I clinical studies with aplidine, L-carnitine was given as a 24 hour pretreatment or co-administered to prevent myelotoxicity, see for example WO 02 30441. Co-administration of L-carnitine was proven to be able to improve the recovery of the drug induced muscular toxicity and has allowed for dose escalation of aplidine.
Thus in clinical Phase I studies aplidine was not myelotoxic at maximum tolerated doses, except for mild lymphopenia. These characteristics make aplidine a potentially useful agent for the treatment of leukemia. Adding aplidine to the current chemotherapy for leukemia could improve efficacy without the necessity of dose reductions of drugs with proven antileukemic activity, because of increased myelotoxicity. This seems especially relevant for the treatment of relapsed ALL and newly diagnosed and relapsed AML, since these are diseases with a relatively poor prognosis, which are currently being treated with myelotoxic drug combinations.